Statin Drugs and Botanicals Anti-Inflammatory Effects

For those of us with heart disease requiring cardiac bypass surgery (CABG), The New York Times advises we all take statins drugs, since studies show 50% reduction in mortality for those taking statin drugs after CABG.(1) I was somewhat amazed and perplexed by this, since I had already written a previous articleridiculing the idea that statin drugs prevent surgical complications. Now I thought I might have to eat my hat and issue a retraction. Header image: Cardiac Bypass Operation courtesy of wikimedia commons.

Pleiotropic Effects

The two studies on this statin drug benefit for cardiac bypass by Curtis and Barakat refer to the anti-inflammatory “pleiotropic effects” of statin drugs. Cardiac bypass is associated with massive release of proinflammatory cytokines and intense systemic inflammatory response.(2,3) Statin drugs can help with all this inflammation by down regulating Nuclear Factor Kappa Beta (NF-κ B), the master controller of the inflammatory response.(2,3) So, yes, there is a potential benefit for Statins as anti-inflammatory agents. Statin drugs block the inflammatory cytokine release in the post operative patient, thus reducing mortality from the procedure.

Lipophilic statin drugs such as atorvastatin, simvastatin seem to work best. Surprising, the authors comment that there was no proven reduction in myocardial infarction post cardiac bypass with statin drug use. This was a disappointment. The reduction in mortality and episodes of atrial fibrillation was thought to be due to reduction in systemic inflammatory response.(2,3)

Since it appears that the benefit of statin drugs in this population is not as a cholesterol reducing agent. The benefits are due to anti-inflammotry properties of statins. If so, then one might consider other anti-inflammatory interventions which down regulate NFkB. Here is a list of widely available Botanicals which exert anti-inflammatory effect by down regulating Nuclear Factor Kappa Beta (NF-κ B) .

Curcumin

Ginger (Zingiber officinale)

Holy Basil (Ocimum )

polygonum cuspidatum

Berberine (Coptis Chineensis and Barberry, Oregon grape)

Oregano

Chinese Skullcap (Baicalein Oroxylin A)

Rosemary

Although these can be purchased separately on Amazon or your local vitamin store, New Chapter has created a combination product which includes them all in product called Zyflamend, containing a shopping bag of herbal extracts. Some are super critical extracts, revealing the higher quality of the product.

Blocking Inflammation by

Down Regulating Nuclear Factor Kappa Beta

Inflammation triggered by Nuclear Factor Kappa Beta (NF-κ B) is up-regulated in many other diseases such as osteo-arthritis, viral infections and cancer, so you might predict that many of the individual components of Zyflamend are useful for them all. You would be quite correct.

Zyflamend, or the individual components would be useful for reducing joint inflammation associated with cartilage loss in osteoarthritis or rheumatoid arthritis. For example, Curcumin alone has been proposed as a new paradigm in the management of osteoarthritis. (56) Many of the testimonials on the Amazon Zyflamend product page are from people attesting to good results for arthritis relief.(56)

Anti-Cancer Studies – Prostate Cancer

Most of the anti-cancer effects of Zyflamend have been prostate cancer models, with considerable benefits(4-8) Thus this product, or something similar, would be an excellent choice for a “Watch and Wait” nutritional program for elevated PSA. A few other items such as Pterostilbene and Serrapeptidase would be included. We have followed a number of men with this scenarios and all PSA’s have remained stable or decreased over time. (see my article on Pterostilbene for prostate cancer prevention)

If cardiovascular disease and atherosclerosis is caused by inflammation, as many now believe, this would explain many of the benefits of statin drugs which are, after all, anti-inflammatory drugs. Statins were originally developed as an anti-cholesterol drug, it was only much later that the anti-inflammatory effects were discovered.

Perhaps anti-inflammatory herbals such as Zyflamend would be more effective than Statin Drugs with fewer adverse side effects for reducing calcium score if combined with Aged Garlic and Vitamin K2. We await these studies.

In the mean-time, studies on the Zyflamend individual components such as Berberine have shown remarkable benefits in prevention and treatment of cardiovascular disease.(25-29)

Curcumin has been shown effective in retarding atherosclerosis in an Apo E mouse model of atherosclerosis.(55)

Chinese Skullcap (bacailein) has remarkable benefits for preventing cardiovascular disease by “decreasing the oxidation of LDL and suppressing inflammatory responses in macrophages”.(31)(33-35)

Anti-Viral Herbal Agents

As mentioned in my previous article on Anti-Viral Herbal Agents, Chinese Skullcap has both anti-viral and anti-inflammatory properties. Dr Stephen Buhner mentions in his book the more virulent and deadly viral illnesses such as the 1918 influenza epidemic are so dangerous because of the viral induced “cytokine storm”, a severe inflammatory response which overwhelms and kills the patient. Botanicals like Chinese Skullcap are not only potent anti-viral agents, they also turn off this cytokine storm, thereby exerting powerful anti-inflammatory effects.(31)

Conclusion

One might wonder about the outcome of an NIH funded study comparing the anti-inflammatory effects of statin drugs to a botanical product like Zyflamend in such diverse conditions such as arthritis, atherosclerosis, and cancer, as well as mortality after bypass graft surgery. Perhaps botanicals would have superior anti-inflammatory effects, compared to Statin Drugs, without the adverse effects of CoQ-10 depletion, myalgia, neuropathy, diabetes etc.

However, considering the current state of NIH research funding, this study would never happen. It the mean time, those of us who don’t have the luxury of time will incorporate the anti-inflammatory botanicals into our routines whenever possible.

2) Curtis, Michael, et al. “Effect of Dose and Timing of Preoperative Statins on Mortality After Coronary Artery Bypass Surgery.” The Annals of Thoracic Surgery (2017).
Thirty-day all-cause mortality was significantly lower for patients taking a statin 24 hours or less preoperatively (1.7%) compared with 24 to 72 hours (2.9%), more than 72 hours, or no dose (3.8%). Multivariate analysis of a propensity-matched cohort showed taking statins 24 hours or less preoperatively was associated with reduced 30-day all-cause mortality (odds ratio 0.52, 95% confidence interval: 0.28 to 0.98, p = 0.04) versus more than 24 hours or no dose. For preoperative statin dose, 30-day all-cause mortality was significantly lower when taking 20 mg or less(1.8%) or more than 20 mg atorvastatin or equivalent (2.1%) than when taking none (3.8%). In multivariate analysis of the propensity-matched cohort, more than 20 mg preoperative dose was associated with a 68% reduction of 30-day all-cause mortality (odds ratio 0.32, 95% confidence interval: 0.13 to 0.82, p = 0.02) compared with no preoperative statin. However, a 20 mg or less preoperative dose showed no mortality reduction.

statin benefits may extend beyond lipid control [4, 16]. These lipid-independent mechanisms, called pleiotropic effects, involve antiinflammatory, antioxidant, antithrombotic, and vasodilatory pathways. Specifically, in addition to being a precursor for cholesterol, HMG-CoA is a precursor for other nonsteroidal isoprenoid products (eg, farnesyl pyrophosphate and geranylgeranyl pyrophosphate) [17]. These molecules are essential for the posttranslational modification of intracellular guanosine triphosphate-binding proteins, such as Rho, Ras, and Rac1 GTPases [17, 18]. Rho activates nuclear factor-κB, which signals initiation of several inflammatory responses and the reduction of endothelial nitric oxide synthase [19, 20].

19) Food Chem Toxicol. 2010 Oct;48(10):2872-80. doi: 10.1016/j.fct.2010.07.020. Epub 2010 Jul 18. Aqueous extract of ginger shows antiproliferative activity through disruption of microtubule network of cancer cells.
Choudhury D1, Das A, Bhattacharya A, Chakrabarti G.
Ginger has a long history of use as traditional medicine for varied human disease. Our present study has shown that the aqueous extract of ginger (GAE) interacts directly with cellular microtubules and disrupts its structure and induces apoptosis of cancer cells as well. The IC(50) values of GAE, as determined from cell viability experiment on human non-small lung epithelium cancer (A549) cells and human cervical epithelial carcinoma (HeLa), were 239.4+7.4 and 253.4+8.9 μg/ml, respectively. It has been found that the apoptosis of A549 cells by GAE is mediated by up regulation of tumor suppressor gene p53 and alteration of the normal Bax/Bcl-2 ratio followed by down regulation of cellular pro-caspase3. The morphological change of cells upon GAE treatment has also been demonstrated. Both the structural and functional properties of tubulin and microtubule were lost, as confirmed by both ex vivo and invitro experiments. The major component of GAE is poly-phenols (around 2.5%), which consist of ∼ 80% flavones and flavonols. Poly-phenolic compounds are well known to have anti-mitotic properties, and may be further screened for the development of a potential anti-cancer agent.

29) https://nutritionreview.org/2013/04/drugfree-alternatives-arrhythmia/
Researchers studied the effects of berberine on individuals with ventricular tachyarrhythmias and found that 62% of patients had 50% or greater, and 38% of patients had 90% or greater, suppression of ventricular premature contractions.7 No severe side effects were observed from berberine therapy. In humans with refractory congestive heart failure, berberine produced several significant changes: a 48% decrease in systemic and a 41% decrease in pulmonary vascular resistance, along with a 28% decrease in right atrium and 32% decrease in left ventricular end-diastolic pressures.8 A measurable increase in cardiac index (45%), stroke index (45%), and left ventricular ejection fraction (56%) were also observed. There were increases in the indices of left ventricular performance and a decrease in arteriovenous oxygen uptake (28%) with no changes in total body oxygen uptake, arterial oxygen tension, or hemoglobin dissociation properties.

The flavonoids, baicalin (5,6-dihydroxy-2-phenyl-4H-1-benzopyran-4-one-7-O-d-β-glucuronic acid) 1 and its aglycone, baicalein 2 are found in edible medicinal plants, Scutellaria baicalensis Georgi and Oroxylum indicum (L.) Kurz in abundant quantities. The antioxidant and anti-inflammatory effects of these flavonoids have been demonstrated in various disease models, including diabetes, cardiovascular diseases, inflammatory bowel diseases, gout and rheumatoid arthritis, asthma, neurodegenerative-, liver- and kidney diseases, encephalomyelitis, and carcinogenesis.

These flavonoids have almost no toxicity to human normal epithelial, peripheral and myeloid cells. Their antioxidant and anti-inflammatory activities are largely due to their abilities to scavenge the reactive oxygen species (ROS) and improvement of antioxidant status by attenuating the activity of NF-κB and suppressing the expression of several inflammatory cytokines and chemokines including monocyte chemotactic protein-1 (MCP-1), nitric oxide synthase, cyclooxygenases, lipoxygenases, cellular adhesion molecules, tumor necrosis factor and interleukins. In this review, we summarize the antioxidant and anti-inflammatory effects of baicalin and baicalein with molecular mechanisms for their chemopreventive and chemotherapeutic applications in the treatment of inflammatory-related diseases.

Anti-Aging

32) Rejuvenation Res. 2016 Mar 15. [Epub ahead of print]A Bioinformatic Approach for the Discovery of Antiaging Effects of Baicalein from Scutellaria baicalensis Georgi.
Gao L1, Duan DD1,2, Zhang JQ1, Zhou YZ1, Qin XM1, Du GH1,3.
Aging is one of the most complicated phenomena and is the main risk factor for age-related diseases. Based on the public aging-related gene data, we propose a computational approach to predict the antiaging activities of compounds. This approach integrates network pharmacology and target fishing methods with the aim of identifying a potential antiaging compound from Scutellaria baicalensis Georgi. Utilizing this approach and subsequent experimental validation, it was found that baicalein at concentrations of 0.04, 0.2, and 1 mg/mL extended the mean, median, and maximum life spans in Drosophila melanogaster. Particularly, 0.2 mg/mL baicalein extends the mean and median life spans in male flies by 19.80% and 25.64%, respectively. Meanwhile, it was discovered that baicalein improved fertility in flies. Baicalein exerts antiaging effects likely through attenuating oxidative stress, including increases of CAT activity and GSH level and decrease of GSSG level.

35) O.S. Kim, C.S. Seo, Y. Kim, H.K. Shin, H. HaExtracts of Scutellariae Radix inhibit low-density lipoprotein oxidation and the lipopolysaccharide-induced macrophage inflammatory response. Mol Med Rep, 12 (2015), pp. 1335–1341
Traditional herbal formulas made from Scutellariae Radix (SR), the root of Scutellaria baicalensis, have previously been used in the treatment of inflammatory diseases, such as atherosclerosis. The aim of the present study was to investigate the effects of SR on low-density lipoprotein (LDL) oxidation and inflammation in macrophages, which are early events in the development of atherosclerosis. High-performance liquid chromatography photo-diode array analysis was used to obtain a three-dimensional chromatogram of SR. The antioxidative effects of SR were evaluated by determining its scavenging activities against ABTS and DPPH radicals. The inhibitory effect of SR on LDL oxidation was examined using a thiobarbituric acid-reactive substance assay and a relative electrophoretic mobility assay. In addition, the anti-inflammatory effects of SR were evaluated in lipopolysaccharide (LPS)-induced RAW264.7 murine macrophage cells. The results showed that SR exhibited radical-scavenging activities in a dose-dependent manner; in addition, SR attenuated the Cu2+-induced oxidation of LDL as well as significantly inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in LPS-induced RAW264.7 cells. Furthermore, SR induced the protein expression of heme oxygenase-1 (HO-1) in RAW264.7 cells. In conclusion, the results of the present study demonstrated that SR decreased the oxidation of LDL and suppressed inflammatory responses in macrophages, which occurred at least in part via the induction of HO-1. These results therefore suggested that SR may be a potential therapeutic agent for the treatment of atherosclerosis.

Our previous study revealed that oroxylin A, a naturally occurring monoflavonoid isolated from Scutellariae radix, could inhibit the proliferation of human hepatocellular carcinoma HepG2 cells through inducing the apoptosis in these cells. However, the molecular mechanism of its anticancer activity remains poorly understood and warrants further investigations. In this study, we examined the anti-invasive activities of oroxylin A in vitro. The results showed that oroxylin A suppressed MDA-MB-435 cell adhesion to the fibronectin-coated substrate in a concentration-dependent manner. It inhibited the wound healing migration of MDA-MB-435 cells and invasion of MDA-MB-435 cells through reconstituted extracellular matrix (matrigel). Zymography revealed that oroxylin A decreased the secretion of matrix metalloproteinases-2 (MMP-2) and metalloproteinases-9 (MMP-9). Oroxylin A also inhibited the expressions of MMP-2 and MMP-9 in MDA-MB-435 cells. Additionally, oroxylin A exerted an inhibitory effect on the phosphorylation of extracellular regulated proteinkinases1/2 (ERK1/2). Collectively, these data provided a molecular basis for the antiinvasive effects of oroxylin A. Taken together, these findings strongly suggest that oroxylin A had potential anti-metastatic effect in vitro and shed light on the investigation of oroxylin A on breast cancer metastasis in vivo.

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